Catalytic dehydration process



Patented Sept. 14, 1954 CATALYTIC DEHYDRATION PROCESS George Karmas,Plainfield, N. J., assignor to Ortho Pharmaceutical Corporation, acorporation of New Jersey N Drawing. Application August 7, 1951, SerialNo. 240,801

The portion of the term of the patent subsequent to November 13, 1968,has been disclaimed Claims. 1

This invention relates to the dehydration of tertiary allylic alcoholsand more specifically this invention relates to the dehydration oftertiary allylic alcohols by their reaction with an excess of anisocyanate in the presence of a catalyst.

Heretofore catalysts have been used to promote the formation ofurethanes by the reaction of an alcohol or phenol with an isocyanate,and this reaction resulted in the formation of a stable urethane whichwas not readily decomposed to produce a dehydration product of thealcohol.

In a copending application, Serial No. 657,913, filed March 28, 1946, byWilliam Oroshnik, and now abandoned, it is disclosed that an isocyanateand particularly phenylisocyanate may be used to dehydrate a tertiaryallylic alcohol having the following formula:

Compound II in which X is -01? or and R is a hydrocarbon radical. Thisapplication discloses that the dehydration can be accomplished withoutthe use of a catalyst. Dehydration with an isocyanate and without acatalyst requires considerable time and the yields of dehydrated productvary but are never high; the uncatalyzed dehydrations are unpredictablebacause the same reactants do not always result in identical reactionproducts.

An object of this invention is to dehydrate tertiary allylic alcohols bya catalyzed reaction.

Another object of this invention is to dehydrate tertiary .allylicalcohols by a reaction of the said alcohols with an isocyanate in thepresence of a catalyst.

Still another object of this invention is to dehydrate tertiary allylicalcohols by a reaction of the said alcohols with at least twice theirmolar amount of an isocyanate in the presence of a catalyst.

Other and further objects of this invention will be apparent from thedescription following and from the appended claims.

It has now been discovered that a dehydration product of a tertiaryallylic alcohol is consistently obtained in good yields by reacting anisocyanate, in the presence of a catalyst, with the said alcohol,wherein an excess of isocyanate is used and preferably wherein theamount of the isocyanate used in the reaction is equal to at least twicethe molar amount of the tertiary alcohol. This catalytic dehydrationreaction is rapidly completed in a reproducible manner due to the use ofthe catalyst in the reaction.

The following equations probably represent the course of the reactionwhereby a tertiary allylic alcohol is dehydrated by a reaction with anisocyanate in the presence of a catalyst:

wherein the R groups may be any hydrocarbon radical or hydrogen or anysubstituted hydrocarbon radical in which the substituent group is notreactive with an isocyanate radical and. wherein R may be anyhydrocarbon radical or substituted hydrocarbon radical in which thesubstituent group is not reactive with an isocyanate radical.

The dehydration reaction probably includes the formation of a urethaneas an intermediate reaction product having the following formula:

This intermediate reaction product represents the reaction of onemolecule of isocyanate with the alcohol; the dehydration of the alcoholis accomplished by the reaction of the above urethane with a secondmolecule of isocyanate. Carbon dioxide and a substituted urea arebyproducts of the dehydration reaction.

The dehydration reaction is catalyzed by anhydrous inorganic oranhydrous organic salts of heavy metals and particularly by such saltsof metals of group II of the periodic table and by anhydrous inorganicand organic ferric salts and particularly by ferric halides and halidesof metals of group II. Halides which have been found especially suitableas catalysts are ferric chloride and cadmium iodide; ferric thiocyanateand organic ferric salt such as the ferric salt of acetylacetone havealso been found to give par- 3 ticularly good results in the catalyticdehydration.

The ferric salt of acetylacetone is a chelate compound. Chelatecompounds of ferric iron with beta-diketones and beta-ketoesters are ingeneral good catalysts for the dehydration reaction. Ferric salts oforganic acids such as benzoic acid, phthalic acid and acetic acid;ferric salts of sulfonic acids such as benzene sulfonic acid; and ferricsalts of phenolic compounds such as phenol and cresol are also goodcatalysts for the dehydration reaction.

This invention has been found to have particular application in thedehydration of a divinyl carbinol of the following general formula:

CH3 CH5 Comp und II wherein X represents the groups OR or i? OCRCompound II (methory) was prepared by catalytic reduction of anacetylenlc compound prepared by reacting a-ethynyl- [i-ionol with aGrignard reagent and an ether of a 1,4-chlorohydrin of isopreneaccording to the following equation:

Compound I (methoxy) The reduction product of the acetylenic compoundcould be converted to a compound having vitamin A activity by asimultaneous dehydration and rearrangement; this was accomplished atroom temperature in glacial acetic acid in the presence of a trace ofp-toluene sulfonic acid. By this method a rearrangement occurredsimultaneously with the dehydration and an intermediate dehydrationproduct could not be isolated, but compounds having vitamin A activitywere produced.

The dehydration of compounds such as Compound II may be accomplished bythe practice of this invention with the production of a stable producthaving five double bonds and the same configuration with respect tocarbon structure as vitamin A, and thus the dehydration product then hasthe same number of ethylenic linkages as an ester or ether of vitamin Awhich has the following formula:

and R is a hydrocarbon radical.

The preparation of compounds having the general formula:

CH: CH:

CH3 CH3 H oH=oH-( 3-oEcoHT-o=oi1oHgX H OH: H

Compound I in which X is -OR or 0 will and in which R. is a hydrocarbonradical and the hydrogenation of such compounds to produce Compound IIis described in a copending application, Serial No. 617,666, filedSeptember 20, 1945, by William Oroshnik, and now abandoned. Thefollowing are illustrative methods of the various methods which may beemployed for producing Compounds I and II.

fl-Ionone may be reacted with calcium acetyline as described in acopending application. Serial No. 615,691, filed September 11, 1945, byWilliam Oroshnik, now Patent No. 2,425,201 or with lithium acetylide asset forth in another copending application, Serial No. 655,607, filedMarch 19, 1946, by William Oroshnik, now Patent No. 2,472,310 to producea-ethynyl-fl-ionol. The a-GthYIlYl-fi-iOllOl produced may be reactedwith a metal hydrocarbon or a hydrocarbon metal halide; the hydrocarbonmetal halide used is preferably the Grignard reagent. This reactionproduces, in the preferred form, a double Grignard ofa-ethynyl-fi-ionol, as described in a copending application, Serial No.657,912, filed March 28, 1946, by William Oroshnik, and now abandoned.The general formula below represents the derivative of a-ethynyl-p-ionolproduced by the reaction:

in which M is a metal having a valence not greater than two, Y is ahalogen and R is a hydrocarbon radical; but when M is a metal having avalence of one, Y and R, are non-existent; when M is a metal having avalence of two and Y is a halogen, R is non-existent; and when M is ametal having a valence of two and R is a hydrocarbon radical, Y isnon-existent. In the preferred practice MY is MgBr and R is nonexistent.Among some of the illustrative compounds which may be reacted withoc-GthYIlYl- [3-ionol to produce compounds of the aforesaid formula arediethyl magnesium, ethyl magnesium bromide, methyl lithium, methyl zinciodide, and butyl lithium. These reagents may be represented by thegeneral formula (RMMY, in which R is a hydrocarbon radical, such asmethyl-, ethyl-, benzyl-, and the like, a: is an integer not greaterthan two, M is a metal having a valence not greater than two, and Y is ahalogen if :c is one and the valence of the metal is two, but Y isnon-existent if M is a metal having a valence of one and x is one or ifM is a metal having a valence of two and a: is two.

The compounds represented by the last general formula shown may bereacted with an ester or with an ether of a 1,4-halohydrin of isoprenehaving the following general formula:

CH: z-oHT-( :=oHoH2X in which X is -OR or 0 II OGR and R is ahydrocarbon radical and Z is a halogen. A compound is produced by thisreaction which has the following general formula:

CH3 CH3 CHa $113 H2 CH=CH+CECOHz-G=CH-CHzX OH H2 CH3 Compound I in whichX has the same meaning as before.

The methods for producing the ester and ether of the 1,4-halohydrin ofisoprene are described in the copending applications, Serial No.633,873, filed December 8, 1945, by William Oroshnik, now Patent No.2,541,091 and Serial No. 633,874, filed December 8, 1945, by WilliamOroshnik, now Patent No. 2,511,870.

Compound I may be prepared in other ways. One such method of preparingCompound I is to react the ester or ether of the 1,4-halohydrin ofisoprene with an acetylide such as sodium, potassium, lithium, orcalcium acetylide to produce a compound having the formula:

(1H3 HoEo-oH2-o=oi1omx in which X has the same significance as before.This compound may then be treated with a hydrocarbon metallic halidesuch as alkyl magnesium halide to produce a compound having the generalformula CH3 YM-o=o-oH2o=oHoH1x in which X has the same significance asabove, M is a metal, and Y is a halogen.

Compound I is produced by reacting this compound with ,B-ionone.

Compound I may have its acetylenic bond converted to an ethylenic bondby hydrogenation whereby Compound I is converted to Compound II whichhas four ethylenic linkages and a hydroxyl group, which hydroxyl groupis potentially capable of producing a fifth ethylenic linkage by beingremoved as water. 7

'The following illustrative material illustrates the reactions leadingup to and the preparation of Compound II in which X is ()R and R ismethyl and in which X is 0 O(JR and R is methyl.

Preparation of the double Grignard of ocethynyl-p-ionol.

One mole proportion (218 grams) of a-ethynyl- ,B-ionol is placed in aglass flask. Then about 600 grams of anhydrous ethyl ether, whichdissolves oc-EthYIlYl-fl-iOIIOl, are added. This solution iscontinuously agitated or stirred while two mole proportions of aGrignard reagent, and in this example'267' grams of CzHsMgBr dissolvedin 700 cc. of anhydrous ethyl ether, are gradually added. Aftercompletion of this addition, the mixture is heated to boiling whilebeing continuously stirred and in constant state of agitation and ismaintained in this state of boiling under a reflux condenser for aperiod of approximately thirty minutes to produce a novel reactionproduct which is dissolved in the ethyl ether and which has thefollowing formula:

CH3 CH3 (3113 H CH=CHCCECMgBr OMgBr H CH3 Condensation ofa-ethynyl-p-i'onol double Grignard with1-chloro-2-methyl-4-methoxybutene-Z to form (Compound II-methoxy).

To the reaction mixture containing the double Grignard in ethersolution, and which has been allowed to cool to room temperature, isadded one mole proportion of the methyl ether of the 1,4-chlorohydrin ofisoprene followed by the addition of approximately two grams of cupricchloride as a catalyst. The mixture is stirred under a reflux condenser,and heated to boiling, kept at a boiling temperature under reflux fortwo to four hours, then allowed to cool to room temperature, and finallystirred for fifteen hours. At this point two layers are formed.

Cuprous bromide may also be used to catalyze the condensation. Whencupric chloride is used, a series of color changes from dark red toyellow occur within the first few minutes, but when cuprous bromide isused, there are no color changes, but a gradual solution of the solidtakes place. After approximately three-fourths of an hour a heavy lowerliquid layer is formed. The refluxing with stirring is continued at roomtemperature for fifteen hours in either case. By this time the lowerliquid layer has changed to a tacky reddish mass.

Hydrolysis and purification of the reaction product containing CompoundI (methoxy).

The reaction product containing Compound I (methoxy) is hydrolyzed byfirst chilling to 40 C., and then 1500 cc. of 30% aqueous ammoniumchloride is added slowly and cautiously to the chilled material. Thereaction mixture is allowed 7 to come up slowly to room temperature withstirring and is then stirred until all solid matter has dissolved.

The hydrolysis may be made with aqueous acetic acid, in which case thereaction product is cooled to 10 C. This temperature is maintained foran additional fifteen minutes after addition of the acetic acid iscomplete. In either case the mass is allowed to come to room temperatureand is filtered. The filtrate separates into two layers, an aqueouslayer and an ether layer. The ether layer is separated from the aqueouslayer and washed with water and then with sodium bicarbonate solution,to neutralize any residual acetic acid.

A aqueous solution of ammonium acetate may also be used to hydrolyze thereaction product by following the same conditions as when aqueous aceticacid is used.

The neutral reaction product obtained by the hydrolysis is treated toremove therefrom any unreacted methyl ether of the lA-chlorohydrin ofisoprene which may be present. This may be done by first concentratingthe neutralized ether solution of the reaction mass under vacuum and atroom temperature and then dissolving the resulting concentrate in aboutfive times its volume of diethylamine or ethyl alcohol and diethylaniineand allowing this solution to stand at room temperature for eight totwenty-four hours. This solution is then poured into a large volume ofwater whereupon liquid oily particles separate out and are extractedwith ethyl ether which dissolves the oily material. This ether solutionis separated and removed from the aqueous portion of the mix and is thenwashed with water, with a 5% aqueous solution of acetic acid, with wateragain, and finally with an aqueous solution of sodium bicarbonate. Asmall amount of diethylamine is added to the resultant ether solution,and the solution is dried with anhydrous potassium carbonate or othersuitable drying agent and is filtered; the filtrate is recovered andconcentrated under vacuum at room temperature.

This concentrate consists essentially of Compound A I (methoxy) and isdistilled under high vacuum. The major portion is distilled at 1l5-125C. at mm. and has an index of refraction at 27 C. of 1.5194.

Reduction of Compound I (methoxy) to pro- Case Compound H (methoxy).

Compound I (methoxy) is dissolved in five to ten times its volume ofanhydrous methanol containing 0.07 gram of zinc acetate and 10 cc. ofdiethylamine per 150 cc. of methanol. To this solution is then added 10grams of powdered activated charcoal Norite containing one gram ofpalladium metal uniformly distributed on its surface. This mixture isshaken to thoroughly mix the components and is then shaken under anatmosphere of hydrogen gas at atmospheric pressure. A small amount ofhydrogen is absorbed in this step. To this mixture is added thirty gramsof calcium carbonate powder containing 0.36 gram of palladium hydroxideuniformly distributed on its surface, and this mixture is againsubjected to shaking in an atmosphere of hydrogen at atmosphericpressure. Absorption of hydrogen proceeds rapidly under theseconditions. The quantity of hydrogen is measured continuously, as it isbeing added, by any convenient means. When one mole of hydrogen has beenabsorbed, this operation is stopped, and the mass is filtered and thefiltrate is recovered and consists essentially of a novel compounddissolved in methanol and having the following general formula:

CH3 CH3 Compound II (methozcy) This methanol solution is poured into alarge volume of water which dissolves the methanol and separates the oiltherefrom. To this mass is added ethyl ether which dissolves the oil. Aseparation into two layers, an ether layer and an aqueous layer,results. The ether layer is separated from the aqueous layer and is thenwashed several times with water; it is dried with potassium carbonate orany other suitable drying agent, filtered, and the filtrate is recoveredand concentrated under vacuum at room temperature. The concentrate isthen subjected to high vacuum distillation, preferably at a pressure of.001 or .0001 mm. of mercury pressure, and three fractions are usuallyseparated and collected. One fraction distills at 60-100 C. at apressure of 0.001 mm. of mercury and measures about twentyfive grams; asecond fraction distills at -115 C. at a pressure of 0.001 mm. ofmercury and measures about ten grams; and a third fraction whichdistills at -118 C. at a pressure of 0.001 mm. of mercury and measures260 grams. This third fraction has carbon and hydrogen valuescorresponding to the calculated values of a compound having the formulaof Compound II (methoxy). This third fraction is a golden viscous liquidwhich shows slight absorption of ultra violet light and has an index ofrefraction at 26 C. of 1.5099.

Reaction of 1-chloro-2-methyl-4-acetoxy-butene-Z with the doubleGrignard of a-ethynyl- B-ionol to produce Compound I (acetoxy) Two gramsof cuprous bromide were added to the double Grignard ofoc-BthYIlYl-fl-lODOl, which had been prepared by adding 132 cc. of a1.585 molar solution of ethyl magnesium bromide in ether to 21.8 gramsof oc-SthYIlYl-fi-lOIlOl in 50 cc. of dry ether. The black color of thesolution disappeared immediately after the cuprous bromide had beenadded, and the color of the solution was then light yellow. Eighteengrams of the acetoxy compound, in 20 cc. of ether, were added to theabove solution of the double Grignard of ozethynyl-p-ionol over a periodof about ten minutes and within a very short time after the addition wascomplete a second heavy layer appeared. The solution was stirred undernitrogen for eighteen hours and was then cooled to -20 C. A saturatedsolution of ammonium chloride was carefully added, and the solution wasthen allowed to come up to room temperature. The solution was filtered,washed with water, then alternately with ether and ammonium chloridesolutions several times. The solution was again filtered and the etherlayer was concentrated under vacuum. The residual oil was dissolved in50 cc. of 95% ethyl alcohol and 50 cc. of diethyl ethanolamine. Thesolution was allowed to stand at room temperature for a period of twodays under nitrogen and in the dark. The dark opaque reaction mixturewas poured into several times 7 its volumeof brine solution and wasextracted with petroleum ether. The petroleum ether layer was washedwith dilute acetic acid and then with water and finally with sodiumbicarbonate solution. The solution was dried over potassium carbonateand concentrated under vacuum; it was not purified further. The productof this reaction has the following formula:

w E r H: CH=GH(IJCECOH2G=CHCH2OCCH:

OH H: CH3

CompoundI (acetomy) Reduction of Compound I (acetoxy) to produceCompound II (acetoxy).

The concentrate from the above reaction was dissolved in 150 cc. ofmethyl alcohol containing two grams of acetic anhydride. As a catalyst,one gram of catalytic material consisting of palladium or charcoalwherein of the composition was palladium, 2 cc. of water and 10 cc. ofdiethylamine were added to the concentrate. The concentrate plus thecatalyst mixture were shaken in the presence of hydrogen until an amountof hydrogen slightly in excess of the theoretical amount required toreduce an acetylenic bond to an ethylenic bond had been absorbed. Thecatalyst was then filtered off, and the resulting filtrate was pouredinto brine. This mixture was extracted several times with ether, washedwell with water, and the ether solution was dried over potassiumcarbonate. The ether solution was filtered, concentrated under vacuum,and finally distilled at 10 mm. Three fractions were taken. The firstfraction came over at (SO-105 and had a refractive index of n =1.5128;the second fraction came over at 105-110 and had a refractive index of n=1.5273 and the third fraction came over at 110-150" and had arefractive index of n =1.5390. The third fraction represents the reducedproduct and has the following formula:

Compound II (acetomy) The following exemplary material is given in orderto illustrate the practice of the invention in one of its specificembodiments, and it is not intended that the examples are to beconstrued in a limiting sense.

EXAMPLE I Catalytic dehydration of Compound II (methoxy) Ten grains ofdistilled Compound II (methoxy) dissolved in 1.00 cc. of dry benzene,were added to 20 cc. of phenylisocyanate and 3 mg. of the anhydrousferric salt of acetylacetone were added to the mixture and the whole wasrefluxed for two hours. The benzene and any excess, unreacted isocyanatewere distilled off under vacuum. The residual pasty mass was extractedwith two 100 cc. portions of petroleum ether, boiling at 30-60 C., andthe petroleum ether solution was filtered to remove any insolublediphenylurea. The petroleum ether filtrate was washed with water anddried over anhydrous potassium carbonate. The petroleum ether wasdistilled under high vacuum, and the residue was distilled, The major l0portion distilled at 105-115 C. at 10- mm. and had an index ofrefraction at 25 C. of 1.575.

EXAMPLE II Catalytic dehydration of Compound II (acetorcy) Ten grams ofdistilled Compound II (acetoxy) dissolved in cc. of dry benzene, wereadded to 20 cc. of phenylisocyanate, followed by the addition of 3 mg.of the anhydrous ferric salt of the ethyl ester of acetoacetic acid.This mixture was refluxed for two hours. The benzene and excess ofphenylisocyanate were distilled off under vacuum and the residual pastymass was extracted with two 100 cc. portions of petroleum ether, boilingat 30-60" C. and filtered to remove any insoluble diphenylurea. Thepetroleum ether filtrate was washed with water and dried over anhydrouspotassium carbonate. The petroleum ether was distilled and the residuewas subjected to distillation under high vacuum; the distillate wascontaminated with diphenylurea. The crude prodnot was dissolved in 50cc. of petroleum ether and again filtered from insoluble diphenylurea.The petroleum ether was removed by distillation and the residue wasdistilled under high vacuum. A distillate boiling at 120 C. at 10- mm.was obtained which was free from diphenylurea and which had a refractiveindex of n :l.5692.

The yield of distilled product was 4.5 grams.

This application is a continuation-in-part of my U. S. applicationSerial No. 767,849, filed August 9, 1947, now U. S. Patent No.2,574,484.

What is claimed is:

l. A process for dehydrating a compound having the following generalformula:

CH3 CH3 H2 OH:

wherein X is selected from the group consisting of -OR and O H --OCR andR is a hydrocarbon radical; which comprises reacting the said compoundwith phenyl isocyanate in the presence of a catalyst selected from thegroup consisting of anhydrous chelate compounds of ferric iron withbeta-diketones, anhydrous chelate compounds of ferric iron withbetaketoesters, anhydrous ferric salts of organic carboxylic acids,anhydrous ferric salts of organic sulfonic acids, and anhydrous ferricsalts of phenolic compounds.

2. A process for dehydrating a compound having the following formula:

which comprises reacting the said compound with phenyl isocyanate in thepresence of a catalyst selected from the group consisting of anhydrouschelate compounds of ferric iron with beta-diketones, anhydrous chelatecompounds of ferric iron with beta-ketoesters, anhydrous ferric salts oforganic carboxylic acids, anhydrous ferric salts of organic sulfonicacids, and anhydrous ferric salts of phenolic compounds.

3. A process for dehydrating a compound with the following formula:

which comprises reacting the said compound with phenyl isocyanate in thepresence of a catalyst selected from the group consisting of anhydrouschelate compounds of ferric iron with beta-diketones, anhydrous chelatecompounds of ferric 15 2,540,118

iron with keta-ketoesters, anhydrous ferric salts 12 of organiccarboxylic acids, anhydrous ferric salts of organic sulfonic acids, andanhydrous ferric salts of phenolic compounds.

4. A process according to claim 1 in which the catalyst is the anhydrousferric salt of acetylacetone.

5. A process according to claim 1 in which the catalyst is the anhydrousferric salt of the ethyl ester of acetoacetic acid.

References Cited in the file of this patent UNITED STATES PATENTS NumberName Date Isler Feb. 16, 1951 2,574,484 Karmas Nov. 13, 1951

1. A PROCESS FOR DEHYDRATING A COMPOUND HAVING THE FOLLOWING GENERALFORMULA: